Islet transplantation can restore endogenous insulin secretion in patients with type 1 diabetes (T1D) and consequently enable the attainment of near-normal glycemic control in the absence of severe episodes of hypoglycemia. At the University of Pennsylvania, we have been investigating the efficacy of combined B- and T- lymphocyte directed immunotherapy for promoting immunological tolerance to islet allografts in TID patients (CIT 05). We are also participating in the phase 3 FDA registration trial investigating a T-cell directed immunotherapy (CIT 07), and the islet-after-kidney (lAK) trial in T1D subjects following successful renal transplantation (CIT 06). Penn actively participated in the development of the Consortium Standard Operating Procedures using Serva collagenase in islet manufacturing. Penn became the first center to qualify to proceed with islet transplantations in 2008, and in that year performed three clinical transplants using single islet donors. The initiation of clinical islet transplantation provided the unique opportunity to utilize metabolic and immunologic mechanistic studies to gain insight into beta cell secretory capacity and immunological alterations in lymphocyte phenotype and function after islet transplantation, respectively. Having achieved these milestones of islet manufacturing and transplantation, we are committed to completing the Consortium clinical trials and the accompanying metabolic and immunologic studies. RELEVANCE: Type 1 diabetes (T1 D) results from the selective loss of insulin-producing beta cells in pancreatic islets. Despite a multitude of advanced insulin delivery systems, subjects with TID continue with abnormal fluctuations in glucose level, leading to the development of secondary complications of the disease. Islet transplantation has the potential to provide precise and long term control of glucose metabolism, thus preventing secondary complications of the disease.